The invention relates to new 2,3-benzodiazepine derivatives, their production and use as pharmaceutical agents.
It is already known that selected 2,3-benzodiazepine derivatives have modulatory activity at quisqualate receptors and owing to this property are suitable as pharmaceutical agents for treating diseases of the central nervous system.
It has now been found that the 2,3-benzodiazepine derivatives according to the invention are also suitable for treating diseases of the central nervous system, whereby the compounds are distinguished by better properties compared to the above-mentioned prior art.
The invention relates to the compounds of formula I 
in which
R1 and R2 are the same or different and mean hydrogen, C1-C6 alkyl, nitro, halogen, cyano, the group xe2x80x94NR8R9, xe2x80x94Oxe2x80x94C1-4 alkyl, xe2x80x94CF3, OH or C1-6 alkanoyloxy,
R3 and R4 are the same or different and mean hydrogen, halogen, C1-C6 alkoxy, hydroxy, thiocyanato, C1-C6 alkylthio, cyano, COOR12, PO3R13R14, C1-6 alkanoyl, C1-6 alkanoyloxy, C2-6 alkynyl optionally substituted with C1-4 alkoxy or phenyl, C2-6 alkenyl optionally substituted with C1-4 alkoxy or phenyl; C1-C6 alkyl optionally substituted by halogen, hydroxy, C1-C6 alkoxy, C1-C6 thioalkyl, NR10xe2x80x94R11; C3-7 cycloalkyl, or an optionally substituted aryl or hetaryl radical,
R8 and R9 are the same or different and mean hydrogen, C1-C6 alkyl or the group xe2x80x94COxe2x80x94C1-6 alkyl,
R10 and R11 are the same or different and mean hydrogen, C1-C6 alkyl or C1-6 alkanoyl or together with the nitrogen atom form a 5- to 7-membered saturated heterocyle, which can contain another oxygen, sulfur or nitrogen atom and can be substituted,
R12, R13, R14 are the same or different and mean H or C1-C6 alkyl,
X means hydrogen or halogen,
Y means C1-6 alkoxy or X and Y together mean xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94,
n means 1, 2 or 3, and
A together with the nitrogen forms a saturated or unsaturated five-membered heterocycle, which can contain 1-3 nitrogen atoms and/or an oxgyen atom and/or one or two carbonyl groups or their isomers or physiologically compatible salts.
Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl or hexyl.
R3 and R4 in the meaning of C2-6 alkenyl contain at least one double bond such as, for example, vinyl, propenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-dimethyl-buten-1-yl, 3-methylbuten-1-yl, hexen-1-yl. If R3 or R4 means C2-6 alkynyl, at least 1 triple bond is present, such as, for example, ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl. The alkenyl and alkinyl radicals can be substituted, e.g., with C1-4 alkoxy or phenyl, which can be substituted with halogen. If a halogenated alkyl radical is present, the latter can be halogenated or perhalogenated in one or more places like CF3.
Halogen is defined in each case as fluorine, chlorine, bromine and iodine.
The aryl and hetaryl radicals R3 and R4 can be substituted in one to three places in the same way or differently with halogen, C1-4 alkoxy or C1-4 alkyl.
The aryl and hetaryl radicals can be present as monocyclic or bicyclic compounds and can contain 5-12 ring atoms, preferably 5-9 ring atoms, such as, for example, phenyl, biphenyl, naphthyl, indenyl as an aryl radical, and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, iso-oxazolyl, thiazolyl, isothiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazolyl-5-yl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo[1]thienyl, benzofuranyl as a hetaryl radical with 1-3 heteroatoms such as sulfur, oxygen and/or nitrogen. 2-Thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and phenyl can be mentioned as preferred.
Cycloalkyl is defined in each case as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, especially C3-5 cycloalkyl.
As alkanoyl radicals, straight-chain or branched aliphatic carboxylic acid radicals, such as formyl, acetyl, propionyl, butanoyl, isopropylcarbonyl, caproyl, valeroyl, trimethylacetyl, i.a., are suitable.
If R10 and R11 together with the nitrogen atom form a heterocycle, for example, piperidine, pyrrolidine, thiomorpholine, hexahydroazepine, morpholine, piperazine, imidazolidine, hexahydrodiazepine is mentioned. If the heterocycle is substituted, the substituent C1-4 alkyl or phenyl can be in one to two places, such as, for example, N-methyl-piperazine, N-phenyl-piperazine, 2,6-dimethylmorpholine.
If A together with the nitrogen atom forms a saturated heterocycle, the latter can be substituted at the carbon atom or at another nitrogen atom. In this case, A means, for example, C3 alkylene, which can be substituted with R3 and R4, and in which 1, 2 or 3 alkylene groups can be replaced by oxygen, carbonyl or xe2x80x94NR3xe2x80x94, such as, for example, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94NR3xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94NR3xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR3xe2x80x94COxe2x80x94 or CH2xe2x80x94Oxe2x80x94CR3R4, whereby the carbonyl group is bonded to the nitrogen atom of the benzodiazepine, and R3 and R4 preferably mean C1-4 alkyl. These compounds of formula I contain a chiral center in the 4-position of the 2,3-benzodiazepine skeleton and can be present as a racemate or optical isomers.
If A together with the nitrogen atom forms an unsaturated 5-membered heterocycle, it thus is not a chiral carbon atom, but rather an exocyclic double bond that is present in the 4-position of the 2,3-benzodiazepine skeleton. The unsaturated 5-membered heterocycle can be present partially unsaturated or aromatic. Preferred are heteroaromatic compounds with 1-3 nitrogen atoms, in which A has, for example, the following meaning: 
The physiologically compatible salts are derived from inorganic and organic acids. Suitable are inorganic acids, such as, for example, hydrohalic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or organic acids such as, for example, aliphatic or aromatic mono- or dicarboxylic acids such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example, C1-4 alkanesulfonic acids such as methanesulfonic acid or benzenesulfonic acids that are optionally substituted by halogen or C1-4 alkyl, such as p-toluenesulfonic acid.
The compounds of formula I also comprise all possible stereoisomers and their mixtures, such as diastereomers, racemates and enantiomers.
Preferred are compounds of general formula I in which R2 means hydrogen.
The compounds of general formula I as well as their physiologically compatible salts can be used as pharmaceutical agents owing to their non-competitive inhibition of the AMPA receptors. Owing to their profile of action, the compounds according to the invention are suitable for treating diseases that are caused by hyperactivity of excitatory amino acids, such as, for example, glutamate or aspartate. Since the new compounds act as non-competitive antagonists of excitatory amino acids, they are suitable especially for treating those diseases that are influenced by the receptors of excitatory amino acids, especially the AMPA receptor.
The pharmacological action of the compounds of formula I was determined by means of the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 hours light/dark cycle, with free access to food and water) and their assignment to groups was randomized. The groups consisted of 5-16 animals. The observation of the animals was performed between 0800 and 1300 hours.
AMPA was sprayed into the left ventricles of mice that were allowed to move freely. The applicator consisted of a cannula with a device made of stainless steel, which limits the depth of injection to 3.2 mm. The applicator was connected to an injection pump. The injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow. The animals were observed up to 180 sec. until clonic or tonic seizures set in. The clonic movements, which last longer than 5 sec., were counted as seizures. The beginning of the clonic seizures was used as an endpoint for determining the seizure threshold. The dose that was necessary to raise or reduce the seizure threshold by 50% (THRD50) was determined in 4-5 experiments. The THRD50 and the confidence limit were determined in a regression analysis.
The results of these tests show that the compound of formula I and its acid addition salts influence functional disorders of the AMPA receptor. They are therefore suitable for the production of pharmaceutical agents for symptomatic and preventive treatment of diseases that are triggered by changing the function of the AMPA receptor complex.
The treatment with the compounds according to the invention prevents or delays the cell damage that occurs as a result of disease and functional disorders and reduces the concomitant symptoms.
According to the invention, the compounds can be used for treating neurological and psychiatric disorders that are triggered by overstimulation of the AMPA receptor. The neurological diseases, which can be treated functionally and preventatively, include, for example, neurodegenerative disorders such as Parkinson""s disease, Alzheimer""s disease, Huntington""s chorea, amyotrophic lateral sclerosis, and olivopontocerebellar degeneration. According to the invention, the compounds can be used for the prevention of postischemic cellular degeneration, cellular degeneration after brain trauma, in the case of stroke, hypoxia, anoxia and hypoglycemia and for the treatment of senile dementia, AIDS dementia, neurological symptoms that are related to HIV infections, multiinfarct dementia as well as epilepsy and muscle spasms. The psychiatric diseases include anxiety conditions, schizophrenia, migraines, pain conditions as well as the treatment of sleep disorders and withdrawal symptoms after drug abuse such as in alcohol, cocaine, benzodiazepine or opiate withdrawal. In addition, the compounds can be used in the prevention of tolerance development during long-term treatment with sedative pharmaceutical agents, such as, for example, benzodiazepines, barbiturates and morphine. Moreover, the compounds can be used as anesthetics (anesthesia), analgesics or anti-emetics.
For use of the compounds according to the invention as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable pharmaceutical, organic or inorganic inert media, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene-glycols, etc. The pharmaceutical preparations can be present in solid form, for example, as tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. Moreover, they optionally contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
For parenteral use, especially injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable.
As vehicle systems, surface-active adjuvants such as salts of bile acids or animal or vegetable phospholipids, but also mixtures of them as well as liposomes or their components, can also be used.
For oral use, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable. The substance may also be administered in liquid form, such as, for example, as juice, to which optionally a sweetener is added.
The dosage of the active ingredients can vary depending on method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses.
The production of the compounds according to the invention is carried out for example, in that
a) a compound of formula II 
xe2x80x83in which
R1, R2, X and Y have the above meaning, is cyclized by reaction of
xcex1) Z=COOC1-6 alkyl with R3xe2x80x94Nxe2x95x90Cxe2x95x90O to compounds with A meaning xe2x80x94COxe2x80x94NR3xe2x80x94CO
xcex2) Z=CH2OH or xe2x80x94CH2xe2x80x94NHR3 with phosgene to compounds with A meaning xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94NR3xe2x80x94COxe2x80x94;
xcex3) Z=xe2x80x94CH2OH with R3xe2x80x94COxe2x80x94R4 to compounds with A meaning xe2x80x94CH2xe2x80x94Oxe2x80x94CR3R4, in which R3 and R4 have the above meaning,
b) a compound of formula III or IV 
xe2x80x83in which R1, R2, X and Y have the above meaning, is cyclized by reaction of
xcex1) Zxe2x80x2=xe2x80x94CHxe2x95x90CHxe2x80x94COOC1-6 alkyl with borane-trimethylamine complex and boron trifluoride etherate to compounds with A meaning xe2x80x94(CH2)3xe2x80x94 and xe2x80x94(CH2)2xe2x80x94COxe2x80x94.
Zxe2x80x2=xe2x80x94CHxe2x95x90Nxe2x80x94NH2 in the presence of copper sulfate to compounds with A meaning =CHxe2x80x94Nxe2x95x90Nxe2x80x94.
xcex3) Zxe2x80x2=xe2x80x94Sxe2x80x94C1-4 alkyl with hydrazine hydrate and acid anhydrides or with acid hydrazides to compounds with A meaning xe2x95x90Nxe2x80x94Nxe2x95x90CR3xe2x80x94
xcex4) Zxe2x80x2=xe2x80x94Sxe2x80x94C1-4 alkyl with xcex1-aminoacetals to compounds with A meaning xe2x95x90Nxe2x80x94CR3xe2x95x90CR4xe2x80x94
xcex5) Zxe2x80x2=CH2OH is converted into CH2NH2, the latter is acylated and cyclized to compounds with A meaning xe2x95x90CHxe2x80x94Nxe2x95x90CR3xe2x80x94,
c) a compound of formula V, 
xe2x80x83in which R1, R2, X and Y have the meaning given above, is reacted with xcex1-aminoacetals, xcex1-aminoketals, H2Nxe2x80x94CH2xe2x89xa1Cxe2x80x94R3 or with ammonia and xcex1-haloketones, and then optionally nitro group R1 and/or R2 is reduced, the amino group is acylated or alkylated or converted into halogen or hydroxy or cyano or deaminated or X is dehalogenated simultaneously with the reduction of the nitro group or in succession or hydrogen is substituted by halogen or halogen is exchanged for another halogen, xe2x80x94PO3R13R14, cyano, C1-6 alkanoyl, C1-6 alkanoyloxy, hydroxy, optionally substituted C2-6 alkynyl, optionally substituted C2-6 alkenyl, optionally substituted C1-6 alkyl, C1-6 alkoxy, CF3, C1-6 thioalkyl, COOR12, or Y is re-etherified or the isomers are separated or the salts are formed.
It is advisable to carry out the fusing of the heterocycle on 2,3-benzodiazepines that are suitably substituted in the 4-position.
The reaction of the alkyl radical, in which Z=xe2x80x94COOxe2x80x94C1-6 alkyl, with R3xe2x80x94Nxe2x95x90Cxe2x95x90O in aprotic solvents such as halogenated hydrocarbons at room temperature or a higher temperature results in compounds of formula I with A meaning xe2x80x94COxe2x80x94NR3xe2x80x94COxe2x80x94. If compounds of formula II in which Z=xe2x80x94CH2OH or xe2x80x94CH2xe2x80x94NHR3 are reacted with phosgene in the presence of tertiary amines in inert solvents, such as optionally halogenated hydrocarbons, compounds of formula I with A meaning xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94NR3xe2x80x94COxe2x80x94 are obtained.
If compounds of formula II, in which Z=xe2x80x94CH2OH, are reacted with carbonyl compounds in the presence of acids such as hydrochloric acid, compounds of formula I, in which A means xe2x80x94CH2xe2x80x94Oxe2x80x94CR3R4xe2x80x94, are obtained as cyclization products.
If the 2,3-benzodiazepine in the 4-position contains a formyl group, the latter can be converted in, e.g., a Wittig reaction in the usual way into a compound of formula III, in which Zxe2x80x2=xe2x80x94CHxe2x95x90CHxe2x80x94COOxe2x80x94C1-6 alkyl.
If the acrylic acid ester that is obtained is treated with borane-trimethylamine complex and with boron trifluoride etherate in a halogenated hydrocarbon such as dichloromethane, compounds of formula I are obtained with A=xe2x80x94(CH2)3xe2x80x94 and xe2x80x94(CH2)2xe2x80x94COxe2x80x94, which can be separated by column chromatography. If the 2,3-benzodiazepine that is formylated in 4-position is reacted with hydrazine hydrate, the corresponding hydrazone derivative, which is dissolved in polar solvents and mixed with a solution of copper sulfate in water, is obtained. Compounds of formula I, in which A means xe2x95x90CHxe2x80x94Nxe2x95x90Nxe2x80x94, are obtained as cyclization products.
If a compound of formula III or IV, in which Zxe2x80x2 means C1-4 alkyl-Sxe2x80x94, is reacted with acid hydrazides in the presence of an acid, e.g., sulfonic acid in an organic solvent, compounds of formula I, in which A means xe2x95x90Nxe2x80x94Nxe2x95x90CR3xe2x80x94, are obtained. The reaction can also be performed such that the alkylthio derivative in an organic solvent is heated with hydrazine hydrate, and then is reacted with an acid anhydride to the desired product.
If the methylthio-benzodiazepine derivative is heated with xcex1-aminoacetals H2Nxe2x80x94CR3Hxe2x80x94CHxe2x80x94(O-alkyl)2, H2Nxe2x80x94CH2xe2x80x94CR4xe2x80x94(O-alkyl)2 or H2Nxe2x80x94CR3Hxe2x80x94CR4xe2x80x94(O-alkyl)2 in the presence of an acid, such as p-toluenesulfonic acid, compounds of formula I with A meaning xe2x95x90Nxe2x80x94CR3xe2x95x90CHxe2x80x94, xe2x95x90Nxe2x80x94CHxe2x95x90CR4xe2x80x94 or xe2x95x90Nxe2x80x94CR3xe2x95x90CR4xe2x80x94 are obtained.
The same compounds of formula I can be produced by a compound of formula V being reacted with the corresponding xcex1-aminoacetal NH2CHR3xe2x80x94CR4(OAlk)2 optionally in solvents such as Cellosolve(R) by introducing an inert gas, such as, e.g., argon or nitrogen to remove the hydrogen sulfide or in the presence of sulfur catchers, such as, e.g., mercury oxide. Radical (OAlk)2 is defined as either open or elsexe2x80x94sometimes more advantageouslyxe2x80x94cyclic acetals or ketals. Compounds of formula I can also be produced by compounds of formula V being reacted with propargylamines H2Nxe2x80x94CH2xe2x80x94Cxe2x89xa1CR3 according to processes known in the literature (Eur. J. Med. Chem. 30, 429 (1995) or Ann. Chem. 1987, (2), 103).
Compounds of formula I are obtained even if compounds of formula V with ammonia in solvents such as methanol or Cellosolve(R) optionally are converted under pressure or with the addition of a sulfur catcher, such as, for example, silver triflate or mercury oxide, into the corresponding imine and then reacted with xcex1-haloketones.
If Zxe2x80x2 is a CH2OH group, the alcohol can be converted in a known way by reaction according to Mitsunobu into azide or into phthalimide. Azide can be converted into amine according to methods in literature by reducing agents or by triphenylphosphine. Phthalimide can also be converted into amine by treatment with hydrazine. The acylation of this amine is possible with acid chlorides or acid anhydrides according to known processes. The subsequent cyclization with phosphorus oxychloride results in compounds of formula I with A meaning xe2x95x90CHxe2x80x94Nxe2x95x90CR3xe2x80x94.
The reduction in the nitro group is performed in polar solvents at room temperature or a higher temperature. As catalysts for reduction, metals such as Raney nickel or noble metal catalysts such as palladium or platinum or else palladium hydroxide optionally on vehicles are suitable. Instead of hydrogen, for example, ammonium formate, cyclohexene or hydrazine can also be used in a known way. Reducing agents such as tin(II) chloride or titanium(III) chloride can also be used as complex metal hydrides optionally in the presence of heavy metal salts. Iron can also be used as a reducing agent. The reaction is then performed in the presence of an acid such as, e.g., acetic acid or ammonium chloride, optionally with the addition of a solvent, such as, for example, water or methanol.
If alkylation of an amino group is desired, it can be performed according to commonly used methodsxe2x80x94for example with alkyl halidesxe2x80x94or according to the Mitsonubo variant by reaction with an alcohol in the presence of triphenylphosphine and azodicarboxylic acid ester, or the amine can be subjected to reductive amination with aldehydes or ketones optionally in succession with two different carbonyl compounds, whereby mixed derivatives are obtained [Bibliography, e.g., Verardo et al. Synthesis (1993), 121; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; Micovic et al. Synthesis (1991), 1043].
The acylation of an amino group is carried out in the usual way, for example, with an acid halide or acid anhydride optionally in the presence of a base such as dimethylaminopyridine in solvents such as methylene chloride, tetrahydrofuran or pyridine, according to the Schotten-Baumann variant in aqueous solution at weakly alkaline pH or by reaction with an anhydride in glacial acetic acid.
The introduction of the halogens chlorine, bromine or iodine via the amino group can be carried out, for example, also according to Sandmeyer, by the diazonium salts that are intermediately formed with nitrites being reacted with copper(I) chloride or copper(I) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid or with potassium iodide. Instead of diazonium salts, the triazenes optionally also can be used. If an organic nitrite is used, the halogen can be introduced into a solvent such as, for example, dimethylformamide, e.g., by addition of methylene iodide or tetrabromomethane. The removal of the amino group can be achieved either by reaction with an organic nitrite in tetrahydrofuran or by diazotization and reductive boiling-down of diazonium salt with, for example, phosphorous acid optionally with addition of copper(I) oxide.
The introduction of fluorine is possible by, for example, Balz Schiemann reaction of diazonium tetrafluoroborate or according to J. Fluor. Chem. 76, 1996, 59-62 by diazotization in the presence of HFx pyridine and subsequent boiling-down optionally in the presence of a fluoride ion source, such as, e.g., tetrabutylammonium fluoride.
The replacement of the amino group by the hydroxy group is carried out according to methods that are known in the literature, preferably by conversion into triazine and subsequent treatment with a strongly acidic ion exchanger (according to Tetr. Letters 1990, 4409).
The introduction of halogens into the annelated ring is carried out according to processes known in the literature, e.g., by reaction with N-bromo- or N-iodosuccinimide in polar solvents, such as tetrahydrofuran, acetonitrile or dimethylformamide or else by reaction with iodic acid and iodine according to Lieb. Ann. Chem. 634, 84, (1960).
The exchange of a halogen in the annelated ring is carried out in a way known in the literature optionally under heavy metal catalysis, for example by palladium(II) or palladium(0) compounds by tin-organic or boron-organic compounds, C2-6 alkines, C2-6 alkenes, di- or mon-alkylphosphite, cyanide in solvents such as toluene, tetrahydrofuran or dimethylformamide (M. Kosugi et al. Chem. Lett. 7, 1225, 1984). Optionally, a base, such as, e.g., triethylamine or sodium carbonate, and optionally a co-catalyst, such as, e.g., copper(I) iodide, must be added.
Halogens, such as bromine or iodine, can also be reacted with copper salts, such as copper(I) cyanide (introduction of a nitrile group), copper acetate (introduction of an alkanoyloxy group), sodium alcoholate in the presence of copper(I) iodide (introduction of an alkoxy group) or a mixture of copper(I) iodide and sodium trifluoroacetate (introduction of a trifluoromethyl group).
The halogen can also be subjected to a halogen-metal exchange, e.g., by reaction with butyllithium at temperatures of 0xc2x0 C. to xe2x88x9278xc2x0 C. in solvents such as ether or tetrahydrofuran optionally with the addition of complexing agents such as tetramethylethylenediamine, and then the halogen can be recovered in a way that is known in the literature with electrophiles, such as, for example, dimethylformamide, alkyl halides such as iodides or chlorides, or aldehydes.
The isomer mixtures can be separated into enantiomers according to commonly used methods, such as, for example, crystallization, chromatography or salt formation.
The production of salts is carried out in the usual way by a solution of the compound of formula I being mixed with the equivalent amount of acid or excess acid, which optionally is in solution, and the precipitate being separated or the solution being worked up in the usual way.
In so far as the production of the starting compounds is not described, the latter are known or can be produced analogously to known compounds.
The invention also comprises the compounds of formulas IIa and IIIa, their isomers and salts 
in which
R1, R2, X and Y have the above-indicated meaning and
Zxe2x80x3 means xe2x80x94CH2OH, xe2x80x94CHO, xe2x80x94COOxe2x80x94C1-6alkyl, CH2NHR3, 
xe2x80x83and R3 has the above-mentioned meaning, which represent valuable intermediate products for the production of pharmacologically active compounds. The conversion of the intermediate products into active substances is carried out according to the processes described above.
The production of the intermediate products is carried out according to known methods or methods that are described here. If the 2,3-benzodiazepine in the 4-position contains a methyl group, the latter can be oxidized to formyl with, for example, SeO2. Optionally, the formyl group can be reduced to xe2x80x94CH2OH or oxidized to the carboxyl group, which can then be esterified or the formyl group can be converted into xe2x80x94CH2NHR3 or subjected to a Wittig reaction.
The following examples are to explain the process according to the invention:
I.)
8-Hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
A. 8-Formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
1.0 g (3.1 mmol) of 8-methyl-5-(4-nitrophenyl-9H-1,3-dioloxol[4,5-h][2,3]benzodiazepine (French Patent No. 2566774) is dissolved at 90xc2x0 C. in 15 ml of DMF. 0.38 g (3.4 mmol) of SeO2 is added, and it is stirred for 40 minutes at 90xc2x0 C. After the solid is filtered off, the product is precipitated with 100 ml of water, the crude product is filtered off, and it is washed with water and dried. 1.04 g of the compound is obtained. After purification by column chromatography (silica gel, eluant benzene/ethyl acetate 20:1) and subsequent suspension of the crystalline compound in ethanol, 0.52 g (50%) of product is obtained. Melting point 228-230xc2x0 C. (decomposition).
B. 8-Hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine
A suspension of 7.0 g (20.7 mmol) of the aldehyde that is obtained after reaction step A is cooled to 20xc2x0 C. in 420 ml of ethanol while being stirred and mixed little by little with 7.84 g (0.21 mol) of NaBH4. The reaction mixture is heated to boiling for 1 hour, then mixed with activated carbon and hot-filtered. The solvent is removed, the residue is taken up in dichloromethane, worked up, and 6.37 g (90%) of crude product, which is purified by column chromatography on silica gel with a 1:1 mixture of benzene/ethyl acetate as an eluant, is obtained. 5.46 g (77%) of pure product with melting point 132-134xc2x0 C. is obtained.
C. 8-Hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
1.0 g (2.9 mmol) of the alcohol that is obtained after reaction step B is dissolved in 40 ml of dichloromethane and mixed with 0.5 ml (8.8 mmol) of methyl isocyanate. The solution is allowed to stand at room temperature for 3 days and then concentrated by evaporation. The crystalline residue is suspended in 10 ml of ethanol and heated to boiling. 1.02 g (87%) of yellow product with a melting point of 242-243xc2x0 C. (decomposition) is obtained.
II.)
5-(4-Aminophenyl)-8-hydroxymethyl-7-methylcarbamoyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
A suspension of 1.02 g (2.56 mmol) of 8-hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (stage C) in 40 ml of ethanol is mixed with 0.45 ml (9 mmol) of 98% hydrazine hydrate and RaNi catalyst while being stirred. After 30 minutes, the catalyst is filtered off, and the solution is concentrated by evaporation. The residue is recrystallized in ethanol, and 0.83 g (88%) of product with a melting point of 136-138xc2x0 C. is obtained.
III.)
8-Hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
2.5 g (7.41 mmol) of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (I, stage A) is suspended in THF:water=1:1 and mixed with 0.14 g (3.7 mmol) of sodium boranate while being stirred and cooled to 20xc2x0 C. After 45 minutes of stirring, it is filtered and the crude product is precipitated from the filtrate with 130 ml of water. 2.35 g, which is recrystallized from a mixture of 6.3 ml of dimethylformamide and 1.3 ml of water, is obtained. 1.97 g (78%) of the title compound with a melting point of 175xc2x0 C. (decomposition) is obtained.